SIDNEY ERWIN T. MANAHAN, MD, FPCP, FPRAGout Special Interest Group23 July 2011

HYPERURICEMIA IN CHRONIC KIDNEY DISEASE:DO WE TREAT OR NOT?

URATE POOL

M 800-1500 mgF 500-1000 mg

Renal ExcretionIntestinal Uricolysis

Purine IngestionEndogenous Production

Reutilization

PRODUCTION

ELIMINATION

MAINTAINING URATE HOMEOSTASIS

Objectives

Briefly review renal urate eliminationDescribe renal handling of urate during hyperuricemia and

chronic kidney diseaseReview the evidence on the impact of hyperuricemia on renal

diseasePresent data from intervention studies of urate lowering in

chronic kidney disease

Renal Handling of Urate in Health

Glomerulus

ProximalConvolutedTubule

S1

S2

S3

Uric Acid

100%

1-2%

50%

8-12%

GLOMERULARFILTRATION

REABSORPTION

SECRETION

REABSORPTION

Net Reabsorption

is 90% of filtered urate

FE UA is 10% of the filtered

uric acid

TRANSPORTERSReabsorption• SLC2A9v1• SLC2A9v2• OAT1, 3 and 4

Secretion• MRP4• OATv1

Renal Handling of Urate in Health

Renal Handling of Urate in Disease

Glomerulus

ProximalConvolutedTubule

S1

S2

S3

Uric Acid

100%

1-2%

50%

8-12%

Inhibition of tubular secretion Competitive anions

Enhanced tubular reabsorption Dehydration, diuretics, insulin

resistanceModulation of OAT expression

Sex hormones, aging, diuretic therapy

Mechanisms incompletely defined Hypertension,

hyperparathyroidism, certain drugs and lead nephropathy

Gouty Arthritis

Related?

Tophi

Uric Acid Nephrolithiases

Hypertension

Cardiovascular Disease

Chronic Kidney Disease

URIC ACIDCRYSTALS SOLUBLE

Relationship of HU with disease

HYPERURICEMIA

Hypertension

Cardiovascular Disease

? CAUSE

? CONSEQUENCE

? COINCIDENCE

Chronic Kidney Disease

Interrelationships (HU, CRD, CVD)

CELL

PURINE

URIC ACID

XO

HYPERURICEMIA

SMC Proliferation

Vasoconstriction

RAS Activation

COX2 ActivationHYPERTENSION

ENDOTHELIAL DYSFUNCTION& CARDIOVASCULAR DISEASE

RENAL DISEASE PROGRESSION

Tissue HypoxiaCell DeathInsulin Resistance

MECHANISM FOR RENAL DISEASE

Oxidative StressRAS ActivationRenal Arteriolar DiseaseMacrophage and T cell

ActivationRenal Vasoconstriction

and Ischemia

MECHANISM FOR HYPERTENSION

NOS InhibitionInduction of Endothelial

DysfunctionRAS Activation

Uric Acid, HPN & Kidney Disease

Author Subjects Findings

Hsu et al (2009) 177,570 Volunteers

Risk of chronic kidney disease is 2x in the highest quartile of SUA vs lowest quartile of SUA

Iseki et al (2004) 48,177 Healthy Japanese

HU increased risk of incident ESRD by 3X in males and 10x in females

Obermayr et al (2008)

21,475 Austrians Risk of incident CKD was 63% in SUA >9 mg/dlRisk of incident CKD was 26% in SUA 7-9 mg/dl

Domrongkitchaiporn et al (2005)

3499 Adults Highest quartile of SUA associated with highest risk of CKD and 2.14x risk of ESRD

Weiner et al (2008) 13,338 SUA increase by 1mg/dl confers 7-11% increase in the risk for incident CKD

Observational Studies in Normal AHU

CONCLUSIONIn the general population, higher levels of SUA conferred greater risks for incident CKD and ESRD. The risks appear to affect females more than males.

Author Subjects Findings

Siu et al (2006) 177 Patients Higher SUA associated with doubling of Crea & ESRD.

Syrjanen et al (2000)

223 IgA Nephropathy

HU was associated with risk for progressive CKD.

Tang et al (2009)Park et al (2009)

134 PD patients HU was associated with faster decline in residual renal function and increased endothelial dysfunction

Madero et al (2009) 838 CKD3-4 No association between SUA and progression of CKD. Each 1 mg/dl increase in SUA correlated with 17% increase in all cause mortality & 16% increase in CV deaths.

Observational Studies in CKD-AHU

CONCLUSIONIn the CKD patient, there appears to be no correlation between CKD progression/ ESRD and hyperuricemia. HU was associated with endothelial dysfunction and mortality

No association following adjustment for baseline GFR

Not statistically significant following adjustment for confounders.

Intervention Studies in CKD-AHU

CONCLUSIONIn the CKD patient, treatment with Allopurinol 100-300 mg/d was associated with less progression in CKD and fewer CV events. No impact on BP and proteinuria.

Author Siu et al (2006) Goicoechea et al (2010) Kao et al (2010)

Patients 54 PatientsCrea >120 umol/LU Prot >0.5 g/24h

113 PatientseGFR <60ml/min

53 Patients with CKD and LVH

Intervention Allop100-200 mg OD x 12 months

Allop 100 mg OD x 24 months

Allop 300 mg OD x 9 months

Methodology Open-Label RCT Open Label RCT Double Blind RCT

Outcome 16% in Allop group vs 46% in the control group reached the combined endpoint

12% in the Allop group had a CV event vs 27% in the control group

Improvement in surrogate markers for endothelial dysfunction

SUMMARY

HYPERURICEMIA CHRONIC KIDNEYDISEASE

CAUSE / CONSEQUENCE

Hyperuricemia in the general population increases the risk for CKD and ESRD.

Hyperuricemia in CKD patients was not associated with progression to ESRD. It was associated with increased

risk for cardiovascular events.

Treating Hyperuricemic CKD patients with Allopurinol 100-300 mg/d for 9-24 months preserved renal function and

reduced CV Events

THANK YOU!

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